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Alpha-synuclein: Unlocking the Secrets of a Protein Implicated in Parkinson’s Pathology

What is alpha-synuclein?

Alpha-synuclein (also α-synuclein) is a protein whose function in the healthy brain is not currently known. It is of great interest to Parkinson's researchers because it is a major constituent of Lewy bodies, protein clumps that are the pathological hallmark of PD.

In the several years since its discovery, alpha-synuclein has been the focus of intensive efforts by basic PD researchers working to definitively characterize the protein's role in PD and its potential as a target for neuroprotective therapies. Despite this, there are still more questions than answers as to whether and how alpha-synuclein plays a direct causative role in PD.

Why is alpha-synuclein important?

There is compelling evidence from recent studies that alpha-synuclein may play a role in the development of both (rare) familial and (more common) sporadic cases of Parkinson's disease.

For a very small subset of Parkinson's patients, hereditary variability in the alpha-synuclein gene contributes to developing the disease. In these rare cases of familial PD, the alpha-synuclein gene produces either too much alpha-synuclein protein or an abnormal form of the protein - unusual events believed by some researchers to be toxic to brain cells and to result in neuron dysfunction.

Furthermore, alpha-synuclein is the primary structural component of Lewy bodies, suggesting that protein aggregation plays a role in sporadic Parkinson's disease as well.

These findings support the development of PD therapies that reduce alpha-synuclein gene expression or block its aggregation. Such therapies could potentially prevent or delay the onset of Parkinson's disease, or halt or slow its progression.

A note on Lewy bodies: Many neurodegenerative diseases share the trait of clumping of various proteins, but there is considerable debate among Parkinson's researchers over whether Lewy bodies actually damage cells. While one school of thought is that the clumps are toxic and disrupt normal neuron function, some researchers believe the clumps are protective - the cell's attempt to sequester alpha-synuclein and compartmentalize the potential toxin away from potential targets in the cell structure.

What's more, alpha-synuclein pathology has been found to exist in some body systems not traditionally associated with Parkinson's disease, as well as in patients who did not experience any clinical features of Parkinson's. For this reason, study of alpha-synuclein is crucial to test the emerging hypothesis that Parkinson's affects many areas of the central nervous system beyond the substantia nigra, and even extends beyond the boundaries of the central nervous system. This hypothesis has gained attention in recent years as appreciation has grown for the diversity of the clinical features of Parkinson's.

Finally, research is ongoing to determine whether alpha-synuclein may have a potential use as a biomarker of PD.

What stands in the way of developing new PD therapies that target alpha-synuclein?

Several significant questions about alpha-synuclein's role in the healthy and diseased brain - including what its normal function is and whether blocking its aggregation or lowering its levels in the brain prevents PD progression - remain unanswered. The lack of progressive, predictive animal models of Parkinson's also remains a roadblock to conclusively testing alpha-synuclein-based therapies.

What attempts have been made to develop an alpha-synuclein therapy?

While no drugs targeting alpha-synuclein are yet in the clinic, some approved compounds that have been shown to stop synuclein clumping and to break up existing clumps in vitro are being tested in rodent models. Additionally, a current Michael J. Fox Foundation LEAPS grant aims to develop new small molecules with this potential. Efforts are also under way to determine if it is possible to find molecules that can safely turn down the expression of the synuclein gene, since we know that patients whose alpha-synuclein gene expresses too much of the protein will get the disease.

What is the MJFF view on alpha-synuclein?

A clearer understanding of alpha-synuclein could greatly impact the Parkinson's disease field and help to accelerate a disease-modifying treatment for PD. For this reason, the Foundation's scientific staff and advisors consider alpha-synuclein an exciting research avenue toward our goal of delivering patients better treatments and a cure. MJFF investment in alpha-synuclein is significant, totaling approximately $12 million to date. We target the lion's share of our research dollars at the most translatable aspects of alpha-synuclein science — primarily its potential as a therapeutic target and its possible use as a biomarker.

For more information on MJFF investments in alpha-synuclein research, please search our Funded Studies Database.

April 12, 2007